Our data indicate that lower BMI, nulligravidity, previous uterine surgery, and a thinner endometrial lining during a fresh cycle are associated with inadequate endometrial thickness. In addition, a fresh cycle maximum endometrial thickness of 11.5 mm was found to be a predictor of inadequate endometrial development in a FET cycle indicating that additional estrogen supplementation may be necessary for these cycles. Although the difference we found in fresh cycle endometrial thickness of 10 mm versus 12.9 mm may not represent a clinically significant difference in implantation rate or pregnancy outcome, it may indicate impaired endometrial development.
Bromer et al. also found a positive correlation between endometrial thickness and BMI in patients undergoing clomiphene citrate or FSH treatment . We did not find a significant difference in adequate endometrial development based on age or fertility diagnosis as this group. However, it is possible these patients in our study required additional estrogen during the FET preparation to attain adequate endometrial thickness, and therefore, masking the difference.
When endometrial development is inadequate, it is reasonable to continue estrogen supplementation at the same dose. A potential alternative to unresponsive endometrium is a trial of estradiol via a different route of administration. Because transdermal estradiol does not undergo liver metabolism, there is lower conversion to estrone, and possibly a varied effect on the endometrium . With both interventions, most patients in our study ultimately demonstrated adequate endometrial development and thickness (Figure 1).
Endometrial thickness has long been used as a marker of adequate receptivity of the uterus and as a prognostic factor in embryo transfers. Several studies suggest that pregnancy is less likely when the endometrium is < 8 mm [5–8]. Endometrial thickness < 8 mm does not exclude the possibility of pregnancy, but it is less optimal. In the search for additional markers of success, recent studies have focused on endometrial patterns and sub-endometrial blood flow as a useful adjunct in predicting successful IVF outcomes. A study by Singh et al., looking at endometrial thickness, pattern and sub-endometrial blood flow found a higher pregnancy rate when blood flow to the endometrium was in Zone III (Inner hypoechogenic zone of vascular penetration). They also found that pregnancy rates were highest with an endometrial thickness between 8-10 mm . Chen et al., recently evaluated the combined analysis of endometrial thickness and pattern in predicting outcome of IVF. The author noted that a no triple line endometrial pattern even with a moderate endometrial thickness of 7-14 mm had a detrimental effect on pregnancy outcome, although not the occurrence of pregnancy . They concluded that when a thinner endometrium (< 8 mm) and no triple-line endometrial pattern coexist in an IVF candidate, cryopreservation should be recommended. Despite these findings supporting the importance of endometrial thickness and development, it is important to note that these are surrogate markers of IVF success. Endometrial thickness, in addition to other factors, should be considered.
Several endometrial preparation protocols are utilized, as well as multiple other compounds to attain proper endometrial development. Low-dose aspirin supplementation in women with impaired uterine perfusion may improve uterine blood flow and lead to pregnancy rates similar to women with normal uterine perfusion . Women with uterine fibrosis or thin endometrium for unknown reasons may benefit from prolonged treatment with pentoxifylline and tocopherol [15, 16]. Takasaki et al. showed improvement in endometrial thickness and uterine radial artery resistance after treatment with either vitamin E, I-arginine or sildenafil citrate . Granulocyte colony-stimulating factor (G-CSF) was also recently shown to increase endometrial thickness .
FET is an effective, efficient and affordable means of attaining pregnancy for the patient undergoing IVF. Cryopreservation allows for a decrease in the number of embryos transferred in IVF cycles, while the ability to use preserved embryos in the future leads to an increase in cumulative pregnancy rates. In the patient undergoing FET, predictors of inadequate endometrial development, and potentially inadequate thickness, may help the clinician to be aware and prepared prior to initiation of a new cycle.
Endometrial thickness remains an easily measured and long-employed method of predicting endometrial readiness. In FET cycles in our center, we found that one factor influencing endometrial development is previous endometrial thickness < 11.5 mm. This provides important information for the clinician as these patients may require additional estrogen supplementation. Preparation of the endometrium for FET is the only easily modifiable factor to improve ECT. Other potential factors we identified that can be modified are lower BMI and uterine surgery. Good surgical technique to prevent synechia is critical for adequate endometrial development and should always be practiced. However, in women who have already undergone surgery, this is no longer modifiable. Our data suggests that lower, although normal, BMI is associated with a thinner endometrium. Recommending weight gain would not be appropriate to improve endometrial thickness, and therefore, BMI is not easily modifiable. Our study assists in cycle planning and preparation, and therefore, may decrease prolonged cycles or cancellation and limit costs related to extra visits, ultrasounds and monitoring.
In addition, future study of the employment of ultrasound evaluation of blood flow and pattern would be helpful to determine its utility in making decisions regarding embryo transfer. More research is needed to better understand the mechanism of decreased endometrial thickness as well as how to optimize pregnancy in these patients.